title: microRNA-34a promotes DNA damage and mitotic catastrophe.
abstract: Efficient and error-free DNA repair is critical for safeguarding genome integrity, yet it is also linked to radio- and chemoresistance of malignant tumors. miR-34a, a potent tumor suppressor, influences a large set of p53-regulated genes and contributes to p53-mediated apoptosis. However, the effects of miR-34a on the processes of DNA damage and repair are not entirely understood. We explored tet-inducible miR-34a-expressing human p53 wild-type and R273H p53 mutant GBM cell lines, and found that miR-34a influences the broad spectrum of 53BP1-mediated DNA damage response. It escalates both post-irradiation and endogenous DNA damage, abrogates radiation-induced G 2/M arrest and drastically increases the number of irradiated cells undergoing mitotic catastrophe. Furthermore, miR-34a downregulates 53BP1 and inhibits its recruitment to the sites of DNA double-strand breaks. We conclude that whereas miR-34a counteracts DNA repair, it also contributes to the p53-independent elimination of distressed cells, thus preventing the rise of genomic instability in tumor cell populations. These properties of miR-34a can potentially be exploited for DNA damage-effecting therapies of malignancies.
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology; University of Virginia; Charlottesville, VA USA; Aging-Cancer Interface Group; LDS Medical Center; St. Petersburg, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kofman
authors.forename: Jungeun
authors.initials: J
authors.lastname: Kim
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Evan
authors.initials: E
authors.lastname: Dupart
authors.forename: Christopher
authors.initials: C
authors.lastname: Letson
authors.forename: Yongde
authors.initials: Y
authors.lastname: Bao
authors.forename: Kai
authors.initials: K
authors.lastname: Ding
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: James
authors.initials: J
authors.lastname: Larner
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008938:Mitosis; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53
keywords: 53BP1; DNA damage; brain tumors; microRNA-34a; mitosis; mitotic catastrophe